Substituted glycinamides



Patented Oct. 23, 1956 SUBSTITUTED GLYCINAMIDES William F. Bruce, Havertowng'andJoseph Seifter, Willow Grove,- Pa., assignors, bymesne assignments, to Ameri= can Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application January 3, 1951 Sel'ial No. 204,266

6-Claims. (CL 260-247.2)

This invention relates to new substituted'glycinamides having-the generalformula;

and more specifically by glycinamides having-the formula It has been'observed by some investigators that a limited number of glycinamide derivatives evidence some local anesthetic action although. a systematic studyot the pharmacological actions of substituted. glycinamides had never been reported.

We have found in the preparation-and athorough study of -a' :considerablenumber of new; substituted glycinam= ides that a number of these'compounds evidence marked pharmacological actions hitherto unsuspected in the art and which we consider to behi'ghlyuseful in the medicinal field: Specifically; we havefound that when" particular amines'are"used-inthe' preparation of the'compounds of our invention, the glyciriamide products evidence" useful pharmacological action, more"specifically' described be low? The-'newcompounds of'this invention have the general" formula asindieated above where'RrR'zN may'bea radical selected fromthe'class of nitrogen-containing heterocyclic' radicals or a radical Where R1 and R2 are alkyls; Ysta'nds for a lower alkylene groupand'preterably CH2, the first member of the .gr'oup; while Rs stands for' an. aralkylradical with thealkyl portion -being a' l'ower alkyl either of the straight chain or branched chain type. HydroXy and alloxy substituted. aralkyls are also contemplated.

whenKlRzN'represents a nitrogen-containing harem cyclicradical; the latter may comprise a 5 or 6 membered ring? As" examples of five membe'red' rings contemplated by,this inventionfmay'be'mentioneda triazole, themeducedtriazol'es,pyrroline, pyrrolo'dihe, imida'z oline and I imidazol'idinel As examples of-sixmernbered ringscontemplated by the invention are piperidine, morpholine and"thiomorpholine. The 5 'or 6 membered ring may. have a'benzen'e nucleusfused to the ringras for example, b'nZO'triaZOIeL' It may contain in addition to nitrogen, oxygen "or'sulfur a's part-of the ring structure. Moreover, the alkyl; aralkyl oxy, hydroxy and alloxy derivatives of the ring are :also contemplated. The important limitation is that when R1R2N represents the .residue of a nitrogen-containing heterocyclic, the heterocyclic compound used to form the substituted glycinamide must be the equival'ent ofi a secondary amine.

When RiRzN "represents a radical where Ri and-Rh are' alkyls, the latter may be of the straight-chainor branched-chain type but in any case allryls of more than 9 carbon atoms'are'not contemplated since higher alkyls are difiieult to evaluate pharmacologically *due to solu-" bility problems.

It is-further within the scope ofthis'invention that when" Ri and represent alkyl radicals that Ri and 'R2 may; besimilar or dissimilar radicals;

In general,- 5 the compounds of the invention "may" be 2v synthesized -by reacting an appropriate chloracetamide corresponding to the formula where R3 represents the radicals indicated above with an appropriate secondary amine corresponding to th e for mula RIRZNH, whereRiRzN represents the radicals as indicated above. q

The amines may be prepared in the usualand-known manner. The preferred method for the preparation of the chloracetamide intermediate involves reacting chlor acetyl chloride with a primary amine R3NH2 in the presence of benzene or ether as a solvent'for thereactants. Heating may or may not be necessary.depending-on'the speed of the particular reaction. The chloracetamide remains in solution. in the solvent and is obtained by distilling off the solvent under reduced pressure. In gen+ eral, a molar ratio-of chloride to amine of about- 1:2 is preferred for the reaction.

The reaction of. the appropriate chloracetamide-and the appropriate secondary amine toform the-desired-sub stituted glycinamide is preferably operated with a molar ratio, amide to amine 'of =about"1:-l and is carried out in the -presence of a' solvent for the-reactants 1 suchhigher alcohols having 4 to 7 carbon'atoms in the molecule, dioxane or hydrocarbon solvents such as xylene. The reaction iscarr'ied outinthe' presence of an acid acceptor or mildly basic materialsuch' as alkali or alkaline'earthf metal carbonates, sodium" bicarbonate or alkali metalalcoholates and" preferably about 2 to 3 mols of thls mate rialisuse'd; The reaction operationis set up 'for'reflu in g and *the reaction temperatur'e'"'is' the refluxing rem: perature' of "the particular solvent selected. Generally a' reactionor'refluxing time-of about 10-15 hoursissufii cientfor complete reaction." In the event that 'solids are formed, theseareremoved' by filtration, the substituted glycinamide product remaining in solution in" the 'solventi' The latter' is finally removedby distillation at"low*pres sures toohtain-the desired product;

The new compounds have valuable properties; being useful in the preparation of quaternary ammonium com: ounds"; di ratt acidamid, etc. Additionally the are oftemu'sefuhinthat' they possess atleast' one ofthe fol lowing pharmacological actionsz local anesthetic, pressor, s'pasm'ol'ytic, analgesic, sedative and convulsanfactionj It"'is knowntha't certain amines possess a yasocom R1RaNCH2CONH-R3 F 7 that when the radical RiRN- and/or are 'the residuesof"se'condary and primary"'pressor' amine's', respectively; acritically new physiolog'ical' action is found that is unpredictably different from the physiological action of the pressor amines'alon'e. Itsh'ould be pointed out, however, that the use of pressor amines is not invariably necessary in 'or'clerto"ob'tain the substituted glycinamides ofour invention having:zhighlyuse'tul 'physi ological properties.

Proceeding to a better understanding .of the invention, illiist'rative"specific"procedures for the"preparation of representative compounds falling within the general formula are set forth in the following examples.

EXAMPLE I Preparation of alpha-(N-methyFN-Z-heptylamino)-N benzyl acetamide To 400 cc. of butanol contained in a one liter three neck flask, fitted with a mechanical stirrer, reflux condenser, and thermometer, was added 12.9 gms. of N-methyl-Z-amino heptane, 18.3 grns. of chloro-acetobenzylamine and 50 gms. of sodium carbonate. The reaction mixture was heated at 100 C. overnight. It was filtered while hot to remove the inorganic salts. The salts were washed with n-butyl alcohol and the washings added to the filtrate. The filtrate was washed with sodium carbonate solution to remove any halogen which was determined by the Beilstein test. The filtrate was dried over magnesium sulfate and the alcohol distilled off under vacuum. The residue was also distilled under vacuum. B. P., 175-180 C. at .8 mm. N calculated, 10.14%; found, 9.75-9.97%.

In the same manner as indicated above, one may substitute other higher alkyl secondary amines such as the methyl or ethyl amyl, hexyl, octyl or nonyl amines for the methyl heptyl amine used in the specific example.

EXAMPLE II Preparation of alpha-diethylamino-N-(l-methyl-Z-phenylethyl) acetamide For the preparation of the chloracetyl intermediate, a solution of 27 grams of amphetamine in 80 cc. of benzene was added in portions to a solution of 11.3 grams of chloracetyl chloride in benzene. Heat was evolved and the addition was done at a rate which kept the temperature between 50 and 60 C. On standing, solid amphetamine hydrochloride precipitated and was collected on a filter. This weighed 13.5 grams and melted at 149 C. The filtrate, after removal of the solvent in vacuo gave a yellow oil which solidified on standing. It weighed 26 grams and melted at 68 C. It was moderately soluble in cold ethanol and ethyl acetate and readily soluble in chloroform. It was crystallized from ethyl acetate with the addition of petroleum ether. The recrystallized product melted at 7172 C. Analysis showed 6.0% N (calculated 6.6%) proving to be N-alphachloracetyl amphetamine. A sample on distillation boiled at 155l65 C. under a pressure of 3 mm.

A solution of 5 grams of N-alpha-chloracetyl amphetamine and 2 grams of diethyl amine in cc. of n-butanol, together with 2 grams of sodium carbonate was refluxed for 12 hours. The solids were filtered OE and the filtrate was concentrated in vacuo and distilled. The product, alpha-diethylamino-N-(1-methyl-2-phenylethyl) acetamide was a colorless oil boiling at 160-166 C. at a pressure of 4 mm. The yield was 5.4 grams.

EXAMPLE III Preparation of alpha-di-n-amylamino-N-I-methyl-2-phenylethyl acetamide To 200 cc. of n-butyl alcohol contained in a one liter flask equipped with a mechanical stirrer and reflux condenser were added 20 grams of di-n-amylamine-HCI, 22 grams of crude chloro-N-B-phenylisopropylacetamide and 40 grams of dry sodium carbonate.

The reaction mixture was refluxed overnight and then filtered to remove inorganic salts. The Beilstein test was negative, and the butanol was removed by distillation. The product was then fractionated. B. P., 194-6 C., at 1.3 mm.

EXAMPLE IV Preparation of alpha-piperidino-N-(I-methyl-Z-phenylethyl) acetamide A solution of 5 grams of N-alpha-chloracetyl-dlamphetamine (prepared as in Example II) and 2 grams of piperidine in 25 cc. of n-butanol together with 3 grams of sodium carbonate was refluxed for 12 hours. The solids were filtered off and the filtrate concentrated and distilled. The product was a viscous, colorless oil boiling at ll85 C. at a pressure of 3 mm. The yield of alpha-piperidino-N-(1-methyl-2-phenylethyl) acetamide was 5.3 grams.

EXAMPLE V Preparation of alpha-piperidino-N-(Z-phenylethyl) acetamide For the preparation of the chloracetyl intermediate, 30 grams of beta-phenylethylamine in 300 cc. of benzene was added slowly with stirring to a solution of 13.5 grams of chloracetyl chloride in cc. of benzene. The reaction was rapid and after cooling beta-phenylethylaminc hydrochloride was filtered off and the filtrate concentrated in vacuo and distilled. The product boiled at -166" C. at 3 mm. of pressure. The yield of N-alpha-chloracetyl-beta-phenylethyl amine was 20 grams.

A solution of 10 grams of N-alpha-chloracetyl-betaphenylethyl amine and 4.3 grams of piperidine, together with 4.5 grams of sodium carbonate, in 25 cc. of n-butanol was refluxed for 12 hours. The organic layer was washed with water, whereupon the product crystallized and was collected on a filter. The product melted at 43-44 C. The yield of alpha-piperidino-N-(2-phenylethyl) acetamide was 6 grams.

EXAMPLE VI Preparation of alpha-(N-methyl-N-Z-heptylamino)-N-diphenylmethyl acetamide To 150 cc. of n-butyl alcohol contained in a 500 cc. flask equipped with a mechanical stirrer and reflux condenser were added 13 grams of N-methyl-Z-amino heptane, 25 grams of chloro-N-diphenylmethylacetamide and 30 grams of sodium carbonate.

The reaction mixture was refluxed overnight and then filtered to remove inorganic salts. The Beilstein test was negative and the butanol was removed by distillation. The product was fractionated. B. P., 220 C. at 1.9 mm.

EXAMPLE VII Preparation of alpha-(N-methyl-N-Z-heptylamino)-N-1- methyl-Z-phenylethyl acetamide To 500 cc. of n-butyl alcohol contained in a one liter three-neck flask fitted with a mechanical stirrer, reflux condenser, and thermometer were added 13 grams of N-rnethyl-Z-amino heptane, 21 grams of chloro aceto Benzedrine, and 50 grams of sodium carbonate.

The reaction mixture was heated at 100 C. overnight. It was filtered hot to remove the inorganic salts. The salts were washed with n-butyl alcohol and the washings added to the filtrate. The filtrate was washed with sodium carbonate solution to remove any halogen which was determined by the Beilstein test. The alcohol was distilled off under vacuum. The residue was also distilled under vacuum. B. P., -177" C. at 0.6 mm.

EXAMPLE VHI Preparation of alpha-(N-methyl-N-Z-heptylamino)-N- omega-phenyl tert.-butyl acetamide A solution of 67 grams of omega-phenyl-tertiary-butylamine in 500 cc. of toluene maintained at 20 C. was treated dropwise with 25 grams of chloracetyl chloride. The precipitated amine salt was filtered off and washed with toluene. The filtrate was concentrated in vacuo and the residue was distilled, boiling from 129130 at 1 mm.

To 400 cc. of butanol contained in a one liter threeneck flask, fitted with a mechanical stirrer, reflux condenser and thermometer, was added 6.8 grams of N-methyl-Z-amino heptane, 12 grams of chloro-N-omegaphenyl-tert.-butyl acetamide, and 50 grams of sodium 5, carbonate: The reactiommixture was heatedat" 100* overni'ghtf Itwas'--filtered--while hot to remove-"the in-" organicsalts: Theisalts werewash'edwith' n butyl alcohol and* the :washings "added to the 'fil'trate'. washed with sodium-carbonate" solutiontd remove anyhalogen:which-was'determined tb'yjthe 'Beilstein test. The

filtrate-was dried over magnesium sulfate "and the alcohol distilled ofi under vacuum. The residue-was'also'dis tilledundervacuum; BEPF, 153'-159"*C.' at .2 mm.

EXAMPLE .IX'

Preparation ofalpha=morphlirio-N iliphanylmethyl acetamide To 400.cc.. ofibutanol contained in. a.one. literr-threeneck flask, fitted with a mechanical stirrer, refluxconr. denserland .thermometer, ..was. added..8.7 grams of morpholi iie, 26 grams of chloro-N-diphenylmethyl acetamide and 50 grams of sodium carbonate. The reaction mixture wasaheatedzat 110019 C. overnight..- It was: filtered hot to removethe.inorganicsalts.-. Thesalts were washed with butanol and the washings added'to thefiltrate. The filtrate-waswashed with sodium car'bonate solntioni to remove: any halogen, which was: determined by the Beil steinztesta The filtratewas dried over: magnesiumfsulfate andithe alcohol-distilled'ofl under-:va'cuum. Theresidue solidified and was-.recrystallized sfro'man-hexane'. M.- .Pl', 9394 C.

EXAMPLE" X Preparationz-of alpha-7-theophyllinaN-diphenylmethyl acetamide To 400 cc. of n-butyl alcohol contained in a one liter flask, fitted with a mechanical stirrer and reflux condenser, were added 20 grams of theophylline, 25 grams of chloro-N-diphenylmethyl-acetamide and 50 grams of sodium carbonate. The reaction mixture was refluxed overnight. It was filtered hot. The solid was washed with water to remove the inorganic salts. It was then washed with ether and dried. M. P., 290-291 C. Analysis: N, calculated 17.36; found 17.17; 16.90.

EXAMPLE XI Preparation of alpha-pyrryl-N-I-methyl-2-phenylethyl acetamide To 200 cc. of liquid ammonia and 0.3 grams of ferric chloride contained in a one liter three-neck flask, fitted with a mechanical stirrer, Dry-Ice condenser and a stopper, was added 5.8 grams of sodium in small pieces. When the sodium dissolved, 200 cc. of toluene was added and the Dry-Ice condenser replaced with a reflux condenser. The ammonia was evaporated oif on a steam bath. While the reaction flask was still on the bath, 18 grams of pyrrole dissolved in 25 cc. of toluene was added through a dropping funnel. It was heated until no ammonia was given off. Then 52.8 grams of chloro-N-lmethyl-Z-phenethyl acetamide dissolved in 150 cc. of toluene was added and the mixture heated for 2 hours. It was then cooled, filtered and the toluene distilled off under vacuum. The residue solidified. It was recrystallized from ethanol. M. P., 134-135 C.

EXAMPLE XII Preparation of alpha-pyrrolidino-N-l-methyl-2- phenylethyl acetamide To 150 cc. of n-butyl alcohol contained in a 300 cc. three-neck flask, fitted with a mechanical stirrer, reflux condenser, and a thermometer, was added 5.6 grams of pyrrolidine, 19 grams of chloro-N-1-methyl-2-phenylethyl acetamide and 20 grams of sodium carbonate. The reaction mixture was heated at 100 C. overnight. It was filtered hot to remove the inorganic salts. The salts were washed with sodium carbonate solution until no halogen was present, which was determined by the Beilstein test. The filtrate was dried over magnesium sulfate andthe-alcohol distilled olf 'under vacuums The prodiict was'fractionated; BE'PI, 168 169 C. at 0.8 mme" EXAMPLES. XIIII',

Preparation of- S-methyl-I,2,3,4-tetrahydrb-Z isoquiniliizo N-Z-phenylisopropyl kzcemmide T6 400cc. of b'iitanol contained "in acne liter, threeneck flask, fitted 'With a mechanicalstirrer, reflux condenser, and thermometer was added 15"grams of3 h1ethyl- 1,2,3,4-tetrahydroisoquinoline, 22'grams of-chloro aceto benzedrine, and 50 gramsof sodium carbonate. Thereaction mixture was heated at'-l00'"overnight.' Itwas filtered-hot to remove-the inorganic salts. Thesalts were washed with-butanol andthe washings, adde'dto the fil trate. The filtrate was washed withsodium hydroxide solution to remove any halogen which was determined by the Beilstein test. The filtrate was. dried over mag nesium sulfate and the alcohol distilled offl'imder vacuum; The residue was then fractionated. Bi Pf, 197 20'3" at 0.5 mm.

EXAMPLEJXLV" Preparation of piperidiiw-N-betae(3,4=dimethaxye phenyl') ethyl acetamide To 45.25 grams of beta=(3,4-dimethoxyplrenyl)ethyl amine dissolved in'"150 cc; of toluene'was' added 17 grams 27.87 grams oi'chloracetylchloride, with stir'ring." After warming to room temperature'the' solution was' washed with water; The chloro-N'-beta=( 3,4'-'dinre'thoxyphenyl) ethyl "acetamide"crystallized'-fronr tnetoluene layer? It" was recrystallized from benzene and hexane? Pf 92. C..

To "400' cc. ofamyl alcohol contained "in' 'a .one' "liter,

condenser, and thermometenwas-sadde'd 12.8 grams of chloro-N-(beta-(3,4-dimethoxy-phenyl) ethyl acetarnide) 4.2 grams of piperidine and 40 grams of sodium carbonate. The reaction mixture was heated at overnight. It was filtered hot to remove the inorganic salts. The salts were washed with amyl alcohol and the washings added to the filtrate. The filtrate was washed with sodium hydroxide solution to remove any halogen Which was determined by the Beilstein test. The filtrate was dried over magnesium sulfate and the alcohol distilled off under vacuum. The residue was also distilled under vacuum, and the distillate solidified. It was recrystallized from n-hexane and dried in a desiccator over parafiin shavings. B. P., 206-215 C. at 0.36 mm. M. P. 7577 C.

By procedures analogous to those described in the above examples, the appropriate secondary amine R1R2NH and the appropriate chloracetamide corresponding to the formula ClCHzCONHRs where R1, R2 and Rs represent radicals as indicated above, can be reacted to form the following substituted glycinamides representative of those comprehended in this invention.

acet- Substantially all of the products of the invention are high boiling basic liquids of limited solubility. It is contemplated that while the products may be used in their basic form, it is within the scope of this invention that they may be prepared and used in the form of their acid-addition salts. The preparation of such a salt is well-known and generally involves the addition of the selected acid to an ether, alcohol or water solution of the basic product. The acid is chosen to yield a salt which is known to those skilled in the art as being physiologically non-toxic. As examples, the hydrochloride, sulfate or tartrate salts of the new products may be used.

It is further contemplated that those substituted glycinamides, or the non-toxic salts thereof, which are less soluble in dilute acid than 0.5% by weight may be brought into satisfactory solution by the use of solubilizing, surface-active, emulsifying or detergent agents in order to obtain a more complete physiological effect of the specific glycinamide product. Lipoid solvents having a physiologically non-toxic effect such as long-chain fatty acid partial esters of hexitol anhydrides or oxy-alkylene derivatives thereof, vegetable and animal oils and ointment bases such as petroleum jelly or cholesterol are examples of solvents that are considered useful in admixture with the substituted glycinamides for obtaining enhanced physiological effect.

Many modifications of the invention will be apparent to those skilled in the art without departure therefrom or from the scope of the claims, and since the foregoing disclosure has been given by Way of example for clearness and understanding only, no unnecessary limitations should be understood and the appended claims should be construed as broadly as the state of the art permits.

This application is a continuation-in-part of application Serial No. 673,155, filed May 29, 1946, now Patent No. 2,548,863.

We claim as our invention:

1. A compound selected from the group consisting of a glycinamide having the formula l-methyl-2-phenylethyl acetamide.

3. The compound, 04- (3 -methyl-1,2,3,4-tetrahydro-2- isoquinolino)-N-2-phenylisopropyl acetamide.

4. The compound, a-piperidino-N-l-methyl-Z-phenylethyl acetamide.

5. The compound, a-piperidino-N-2-phenylethyl acetamide.

6. The acetamide.

compound, a-morpholino-N-diphenylmethyl References Cited in the file of this patent UNITED STATES PATENTS 2,139,190 Iselin et al Dec. 6, 1938 2,153,707 Becherer et al Apr. 11, 1939 2,293,655 Hentrich et al. Sept. 15, 1942 2,356,587 Hentrich et a1 Aug. 22, 1944 2,520,153 Lawson et al Aug. 29, 1950 FOREIGN PATENTS 210,985 Switzerland Nov. 1, 1940 534,129 Great Britain Feb. 27, 1941 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A GLYCINAMIDE HAVING THE FORMULA 